The anthelmintic Praziquantel has been registered, approved and commercialized in the beginning of the 80's of the last century as a racemate. However, the active molecule (eutomer) is the (R)-enantiomer (P. Andrews, H. Thomas, R. Pohlke, J. Seubert Medical Research Reviews 3, 147(1983)).
Racemic Praziquantel is available by a plethora of processes (see Domling et al. ChemMedChem 2010, 5, 1420-1434). The most developed technical scale processes are the original Merck process and the Shing-Poong process or one of its modifications. The racemic Praziquantel has a repugnantly bitter taste. This leads to acceptance issues—in particular in the treatment of young children. The (R)-Praziquantel eutomer is considered to have a less bitter taste than the (S)-Praziquantel distomer (T. Meyer et al. (2009) PLoS Negl Trop Dis 3(1): e357). Thus, there is a strong demand for a cost efficient manufacturing process for enantiomerically pure (R)-Praziquantel.
Many efforts were spent in the last decades to develop a manufacturing process for (R)-Praziquantel or its analogues. These processes can be divided in two groups, firstly enantioselective synthesis routes and secondly methods using the racemic process in combination with a chiral resolution. So far, a few enantioselective processes have been reported, but all of them are laborious and costly.
Woelfie et al. describe a chiral resolution of the Praziquantel precursor Praziquanamine (1,2,3,6,7,11b-Hexahydro-pyrazino[2,1-a]isoquinolin-4-one) by (−)-dibenzoyl-L-tartaric acid (Resolution of Praziquantel, M. Woelfle, J-P. Seerden, J. de Gooijer, Krees Pouwer, P. Olliaro, M. H. Todd, (2011) PLoS Negl. Trop. Dis 5(9):e1260.doi:10.1371/journal.pntd.000260). This resolution achieves rather low yields due to the fact that two crystallization steps are necessary to reach sufficiently high optical purity. Another problem associated with this procedure is the laborious and time-consuming recycling of (S)-Praziquanamine which could be done using the sequence: acylation, oxidative dehydrogenation, hydrogenation and finally deacylation. Beside this, the recycling of (−)-dibenzoyl-L-tartaric acid causes problems, because it is prone to saponification and trans-esterification. Both aspects are particularly difficult on production scale.
Alberto Cedillo Cruz et al. Tetrahedron: Asymmetry (2014), 25(2), 133-140 describes a chromatographic separation of the diastereomers Naproxen-(R)/(S)-praziquanamide, ((11bS)- and (11bR)-[(2S)-2-(6-Methoxy-2-naphthalenyl)-1-oxopropyl]-1,2,3,6,7,11b-hexahydro-2-4H-pyrazino[2,1-a]isoquinolin-4-one which are synthesized from (S)-Naproxen-acidchloride and racemic Praziquanamine, on an achiral phase. In order to obtain the (R)-Praziquanamine the covalent bond in (11bR)-[(2S)-2-(6-Methoxy-2-naphthalenyl)-1-oxopropyl]-1,2,3,6,7,11b-hexahydro-2-4H-pyrazino[2,1-a]isoquinolin-4-one must be cleaved under drastic conditions (85%-phosphoric acid, 150° C.). This process is laborious and not economic. Furthermore there is no efficient recycling of the undesired (S)-Praziquanamine.
Racemic Praziquantel can be separated into its enantiomers by chromatography. Especially effective on large scale is simulated counter current (simulated moving bed) chromatography (Chi-Bung Chin et al. Journal of Chromatography A, 734 (1996) 247-258, J. Pharm. Sciences 93, 3039 (2004), J. Chrom 634, 215(1993)). The disadvantage of the chiral separation of a chiral API at the final stage is, that the unwanted enantiomer, the distomer, is waste, unless there exists a procedure for recycling. Besides the tedious and practically not applicable sequence: selective dehydrogenation (oxidation by sulfur, Ahmed Muneer et al. PLos One 7(10), e 47224, 2012) of (S)-Praziquantel followed by hydrogenation, there does not exist an easily applicable recycling procedure for (S)-Praziquantel.